Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease distinguished by a specific loss of motor neurons in the brain, brain stem, and spinal cord. Initial symptoms of loss of motor neuron activity, including distal muscle weakness and wasting, increased muscle tone with hyperreflexia, and diaphragmatic and/or bulbar weakness are first noticed at an average age of 55. Death occurs from respiratory failure at an average of 4 years after disease onset. The only recognized treatment for ALS is riluzole which extends survival by only about 3 months with no improvement in motor muscular function.
Although ALS is a rare disease (˜1-2 persons per 100,000 population), an understanding of its pathogenesis is likely to impact other neurological diseases that share some pathological features (e.g., frontotemporal lobal degeneration, Alzheimer's disease, Huntington's disease, spinal motor atrophy and fragile X mental retardation). Approximately 10% of ALS cases are familial and the rest are sporadic. Mutations in the Cu,Zn superoxide dismutase 1 gene (ALS1; SOD1) have been identified in ˜20% of familial and in ˜3% of sporadic ALS patients, making SOD1 mutations the most common cause of this disease. The RNA-binding proteins TDP-43 and FUS/TLS are the next most commonly mutated genes, each of which is responsible for ˜4% of familial cases. A number of dominantly-inherited genes associated with atypical ALS phenotypes are each responsible for 1-3% of ALS cases (e.g., ALS with dementia/parkinsonism: microtubule-associated protein tau (MAPT); progressive lower motor neuron disease: dynactin subunit 1 (DCTN1); ALS8: vesicle-associated membrane protein-associated protein B/C (VAPB); juvenile onset autosomal dominant ALS: senataxin (SETX)).
ALS genes involved in RNA metabolism include TDP-43 and FUS/TLS: two RNA-binding proteins implicated in transcription, splicing, and translation. Both of these proteins are components of stress granules: cytoplasmic foci that are characterized as signaling centers assembled from proteins and untranslated mRNAs in cells exposed to adverse conditions. ALS-linked genes associated with RNA/stress response pathways include: mutant SOD1 which inactivates a retrograde transport pathway that causes proteins to accumulate in the endoplasmic reticulum and trigger the unfolded protein response (UPR), a pro-survival program; vesicle-associated membrane protein (VAPB), an endoplasmic reticulum protein that interacts with ATF6, a UPR-activated transcription factor; senataxin, a DNA/RNA helicase associated with tRNA metabolism and the oxidative stress response; and angiogenin (ANG), a stress-activated ribonuclease that promotes motor neuron survival and extends the survival of SOD1G93A mice in a murine model of ALS. These genes indicate an association between mutations in proteins involved in stress granule formation and ALS, a neurological disorder associated with neuron death.